As preparations for carrying out treatment or prevention of diseases by administering a drug into the living body, for example, there are percutaneous absorption pharmaceutical preparations which not only can avoid metabolism of a drug owing to a first pass effect of the liver and various side effects, but also can continuously administer the drug over a prolonged period of time. Among them, development of adhesive pharmaceutical preparations in which a drug is contained in a pressure-sensitive adhesive has been increasingly carried out because of the easy drug application work and the ability to strictly control the dose.
As the basic characteristics required for adhesive pharmaceutical preparations, pressure-sensitive adhesive characteristics may be mentioned from the practical point of view, in addition to the releasing property and stability of the drug. In developing adhesive pharmaceutical preparations, in order to satisfy these basic characteristics, designing of the adhesive pharmaceutical preparations is carried out by selecting most suitable pressure-sensitive adhesive and additive agent in accordance with the drug. As the pressure-sensitive adhesive, an acrylic pressure-sensitive adhesive and a rubber pressure-sensitive adhesive are mainly used, and from the viewpoint of drug stability in the pressure-sensitive adhesive, the rubber pressure-sensitive adhesive which does not have a functional group is generally advantageous than the acrylic pressure-sensitive adhesive. As the rubber pressure-sensitive adhesive, for example, polyisobutylene (PIB) pressure-sensitive adhesive, styrene-isoprene-styrene (SIS) pressure-sensitive adhesive and silicone pressure-sensitive adhesive may be mentioned, but since the SIS and silicone pressure-sensitive adhesives are difficult to be blended with sufficient fatty acid esters which can accelerate absorption of the drug, and the silicone pressure-sensitive adhesive is expensive, blending and selection of these components are limited and, as a result, degree of freedom of the designing of the adhesive pharmaceutical preparation becomes low. Accordingly, as the rubber pressure-sensitive adhesive, polyisobutylene pressure-sensitive adhesive (to be referred sometimes to as “PIB pressure-sensitive adhesive” hereinafter) is easy to use.
However, since the PIB pressure-sensitive adhesive has low polarity, it has a problem of being low in drug solubility. For the purpose of satisfying releasing quantity and persistency of a drug which are required for the adhesive pharmaceutical preparation, although it is desirable to blend the drug in an amount as large as possible, the amount of the drug is limited in the PIB pressure-sensitive adhesive. Even so, in the case of a drug which is solid at room temperature or around room temperature, it is possible to blend the drug in a large amount of its solubility or more by dispersing the solid drug in the pressure-sensitive adhesive. In such a case, since a part of the drug is dispersed in the pressure-sensitive adhesive in the form of crystals and the like, and the concentration of the drug dissolved in the pressure-sensitive adhesive is low, adhesion strength of the pressure-sensitive adhesive itself is not spoiled. That is, when a drug which is solid at room temperature or around room temperature is used, since it becomes possible to attain the blending of the drug in an amount necessary and sufficient for the treatment or prevention as well as the pressure-sensitive adhesive characteristics from the practical point of view, the poor drug solubility of the PIB pressure-sensitive adhesive does not become a large problem.
On the other hand, there are certain drugs which are liquid at room temperature or around room temperature. In the case of such drugs, blending of a drug and pressure-sensitive adhesive characteristics becomes incompatible when a large amount of the drug exceeding its solubility in a pressure-sensitive adhesive is blended in the pressure-sensitive adhesive. That is, a drug which cannot be sufficiently dissolved in a pressure-sensitive adhesive cannot be dispersed and present in the pressure-sensitive adhesive unlike the case of a solid drug, but flows in a PIB pressure-sensitive adhesive during the storage due to the fluidity of the drug itself to thereby exudes on the surface of the pressure-sensitive adhesive layer. This phenomenon of exuding is called bleed, and when the bleed occurs, surface of the pressure-sensitive adhesive layer is covered with the drug to inhibit contact of the pressure-sensitive adhesive with an adherend, so that the adhesion strength of the adhesive pharmaceutical preparation is considerably reduced. In addition, it not only reduce the adhesion strength to an adherend but also causes reduction of adhesiveness of the pressure-sensitive adhesive for the backing, namely reduction of anchorage property.
As the drug which is liquid at room temperature or around room temperature, free base of bisoprolol may be mentioned, but when a large amount of the free base of bisoprolol is blended in a PIB pressure-sensitive adhesive, it causes a problem in that adhesiveness and anchorage property are reduced due to the generation of bleed. Thus, there is a possibility to contain bisoprolol in an adhesive pharmaceutical preparation in the form of a salt such as bisoprolol fumarate, but a drug in a salt form is low in percutaneous absorption ability.
With the aim of improving reduction of pressure-sensitive adhesion characteristics in the case of blending a large amount of a liquid drug in the pressure-sensitive adhesive layer, Patent Reference 1 discloses a percutaneous composition which comprises one or more drugs wherein at least one of them has a low molecular weight and is liquid at room temperature or about room temperature, and a polymer matrix that contains one or more high shearing resistance polymers. It is described that this high shearing resistance polymer reduces the plasticizing effect of the low molecular weight drug and has the tackiness and shearing force sufficient for applying to human. In addition, it is described in its Examples that an acrylic pressure-sensitive adhesive or a blended pressure-sensitive adhesive of an acrylic pressure-sensitive adhesive with a silicone pressure-sensitive adhesive showed a stringiness suppressing effect. Although polyisobutylene is exemplified as the high shearing resistance polymer, the effect thereof is not verified in the Examples and the like, and PIB pressure-sensitive adhesives are not substantially examined.
In addition, according to a view of the present inventors, although it is theoretically possible to suppress stringiness of a pressure-sensitive adhesive in the case of increased blending amount of a liquid drug, by hardening the pressure-sensitive adhesive through the increase of molecular weight of a high shearing resistance polymer, increase of blending ratio of the high shearing resistance polymer and the like as described in the above-mentioned Patent Reference 1, when the pressure-sensitive adhesive is hardened, adhesiveness of the pressure-sensitive adhesive to an adherend is spoiled and adhesion strength of the adhesive pharmaceutical preparation is reduced. Since the acrylic pressure-sensitive adhesive has an originally high level of adhesion strength, reduction of the adhesion strength does not become a serious problem even when it contains a liquid drug, but in the case of the PIB pressure-sensitive adhesive which has low adhesion strength in comparison with the acrylic pressure-sensitive adhesive, when the PIB pressure-sensitive adhesive is hardened, its adhesion strength is sharply reduced so that assuring of its adhesion strength from the practical point of view becomes difficult. Accordingly, it is difficult to apply the method described in the Patent Reference 1 to the polyisobutylene pressure-sensitive adhesive, and it is the actual circumstances that an adhesive pharmaceutical preparation having sufficient pressure-sensitive adhesion characteristics owing to the combination of the free base of bisoprolol and the PIB pressure-sensitive adhesive, has not been obtained yet.
Patent Reference 1: JP-A-2005-23088